Karen Powers - Academia.edu (original) (raw)

Papers by Karen Powers

The dopamine transporter gene (SLC6A3) is a candidate gene for Parkinson’s disease (PD) on the ba... more The dopamine transporter gene (SLC6A3) is a candidate gene for Parkinson’s disease (PD) on the basis of its critical role in dopaminergic neurotransmission. Previously, we identified 22 SNPs in the 5 0 region of SLC6A3, which segregate as eight haplotypes that differ in transcriptional activity when transfected in rat dopamineproducing cells. In the present work from a case –c ontrol study size of 293 cases and 395 controls, we employed a cladistic approach to examine gene–disease association. First, we found strong evidence of balancing selection in this region, as determined by a Tajima’s D statistic of 2.97 (P < 0.001). Second, we found that the eight haplotypes fit into two main clades and that diplotypes of these clades were marginally associated with PD. Then, after we classified cases and controls by the number of risk alleles, accounting for the well-known 3 0 region VNTR polymorphism, we found that having two or more risk alleles resulted in a modest but significant incr...

The Journal of pharmacology and experimental therapeutics, 1994

The steady-state brain-to-free plasma concentration ratio of valproic acid (VPA) is well below un... more The steady-state brain-to-free plasma concentration ratio of valproic acid (VPA) is well below unity, which suggests that it is efficiently removed from the central nervous system (CNS) by specialized transport processes. The purpose of this study was to determine whether probenecid (PBD)-sensitive anion transporters at the choroidal epithelium and brain capillary endothelium are involved in the clearance of VPA from the CNS of the rabbit. Unlabeled VPA was infused i.v. to achieve a steady-state plasma concentration while a tracer concentration of 3H-VPA was introduced into the ventricles by ventriculocisternal (VC) perfusion. In two treatment groups, PBD was administered by direct placement into the VC perfusate or by a combination of an i.v. priming dose and continuous infusion. In the control group, no other treatments were given. PBD administered by either route had no effect on the steady-state VC extraction of 3H-VPA (approximately 57%). Coadministration of PBD through the VC ...

American Journal of Epidemiology, 2002

A reduced risk for Parkinson's disease (PD) among cigarette smokers has been observed consistentl... more A reduced risk for Parkinson's disease (PD) among cigarette smokers has been observed consistently during the past 30 years. Recent evidence suggests that caffeine may also be protective. Findings are presented regarding associations of PD with smoking, caffeine intake, and alcohol consumption from a case-control study conducted in western Washington State in 1992-2000. Incident PD cases (n = 210) and controls (n = 347), frequency matched on gender and age were identified from enrollees of the Group Health Cooperative health maintenance organization. Exposure data were obtained by in-person questionnaires. Ever having smoked cigarettes was associated with a reduced risk of PD (odds ratio (OR) = 0.5, 95% confidence interval (CI): 0.4, 0.8). A stronger relation was found among current smokers (OR = 0.3, 95% CI: 0.1, 0.7) than among ex-smokers (OR = 0.6, 95% CI: 0.4, 0.9), and there was an inverse gradient with pack-years smoked (trend p < 0.001). No associations were detected for coffee consumption or total caffeine intake or for alcohol consumption. However, reduced risks were observed for consumption of 2 cups/day or more of tea (OR = 0.4, 95% CI: 0.2, 0.9) and two or more cola drinks/day (OR = 0.6, 95% CI: 0.3, 1.4). The associations for tea and cola drinks were not confounded by smoking or coffee consumption.

Human Molecular Genetics, 2006

The dopamine transporter gene (SLC6A3) is a candidate gene for Parkinson's disease (PD) on the ba... more The dopamine transporter gene (SLC6A3) is a candidate gene for Parkinson's disease (PD) on the basis of its critical role in dopaminergic neurotransmission. Previously, we identified 22 SNPs in the 5 0 region of SLC6A3, which segregate as eight haplotypes that differ in transcriptional activity when transfected in rat dopamineproducing cells. In the present work from a case-control study size of 293 cases and 395 controls, we employed a cladistic approach to examine gene-disease association. First, we found strong evidence of balancing selection in this region, as determined by a Tajima's D statistic of 2.97 (P < 0.001). Second, we found that the eight haplotypes fit into two main clades and that diplotypes of these clades were marginally associated with PD. Then, after we classified cases and controls by the number of risk alleles, accounting for the well-known 3 0 region VNTR polymorphism, we found that having two or more risk alleles resulted in a modest but significant increase in PD risk [odds ratio 5 1.58; 95% confidence interval (CI): 1.03-2.40]. Finally, we detected a significant interaction between occupational pesticide exposure in men and the number of risk alleles. Among pesticide-exposed subjects, the odds ratio for having two or more risk alleles was 5.66 (95% CI: 1.73-18.53). Thus, allelic variants in SLC6A3, which affect gene expression, are associated with PD in this population and may interact with occupational pesticide exposure to increase PD risk.

Drug metabolism and disposition: the biological fate of chemicals, 1997

E-Delta 2-valproic acid (E-Delta 2-VPA), a major active metabolite of VPA, has been proposed as a... more E-Delta 2-valproic acid (E-Delta 2-VPA), a major active metabolite of VPA, has been proposed as an alternative to VPA because it is less hepatotoxic and is nonteratogenic. In rodents, VPA and E-Delta 2-VPA have a brain tissue/free plasma concentration ratio less than unity, which suggests rapid removal of the alkanoate anticonvulsants from the central nervous system. This study in rabbits employed a simultaneous iv infusion-ventriculocisternal (VC) perfusion technique to investigate the steady-state kinetics of E-Delta 2-VPA transport at the blood-brain barrier, the blood-cerebrospinal fluid (CSF) barrier, and the neural cell membrane. Probenecid (PBD) was coadministered to probe the mediation of transport by organic anion transporter(s). Rabbits in the control group (N = 6) received an iv infusion of E-Delta 2-VPA to achieve a steady-state plasma concentration of 50 to 60 microg/ml. Blood and cisternal outflow of mock CSF perfusate were continuously sampled. Midway through the expe...

The Journal of Trauma: Injury, Infection, and Critical Care, 1997

Although Cocaine use is common in trauma victims, little is known about how cocaine affects the c... more Although Cocaine use is common in trauma victims, little is known about how cocaine affects the cardiovascular response to trauma and associated blood loss. This study determined the effect of chronic cocaine use on the cardiovascular response to hemorrhage in awake and anesthetized sheep. The hemodynamic and acid-base responses to graded hemorrhage were determined in awake and anesthetized sheep at baseline and after 15 and 18 days of chronic cocaine exposure. Chronic cocaine exposure resulted in a moderate paradoxical bradycardic response to hemorrhage in awake sheep, but did not otherwise alter the hemodynamic response to hemorrhage. In anesthetized animals, cocaine exposure impaired the ability to maintain mean arterial pressure and cardiac output during hemorrhage, and resulted in a marked paradoxical bradycardic response to hemorrhage. Chronic cocaine exposure did not have an important effect on the cardiovascular response to hemorrhage in awake sheep. However, in anesthetized sheep, chronic cocaine exposure diminished the compensatory cardiovascular response to graded hemorrhage.

Respiration Physiology, 1993

Hypoxic pulmonary vasoconstriction (HPV) may be manifest in one of two ways: either an increase i... more Hypoxic pulmonary vasoconstriction (HPV) may be manifest in one of two ways: either an increase in the pulmonary artery pressure, or flow diversion away from the portion of the pulmonary bed with reduced conductance. We tested the hypothesis that the magnitude of the HPV response differs under conditions of constant flow perfusion, where pulmonary artery pressure (Ppa) rises during hypoxia, vs conditions of constant pressure perfusion, where Ppa remains constant and flow (0) is diverted away from the lungs during hypoxia. In isolated, perfused rabbit lungs, the H PV response to four levels of hypoxia (12, 6, 3 and 0~o oxygen) was of greater magnitude and more sustained under conditions of constant pressure perfusion as compared to constant flow perfusion. The possible significance of these findings as they relate to interpretation of studies in both the perinatal and mature pulmonary circulation is discussed.

Parkinsonism & Related Disorders, 2009

Background-Epidemiologic findings suggest that dietary components may contribute to the etiology ... more Background-Epidemiologic findings suggest that dietary components may contribute to the etiology of Parkinson's disease (PD). This population-based case-control study evaluated PD risk and dietary intake of fats, cholesterol and iron. Methods-Newly diagnosed case (n = 420) and age/gender/ethnicity-matched unrelated controls (n = 560) were identified between 1992 and 2006 from the Group Health Cooperative health maintenance organization in western Washington State, and the University of Washington neurology clinic. In-person interviews elicited data on food frequency habits during most of adult life. Nutritional intakes were calculated and analyzed, with adjustments made for total energy intake (the 'nutrition density' technique). Results-Cholesterol intake in the highest quartile compared with the lowest quartile was associated with a decreased risk of PD in men (odds ratio (OR)=0.53, 95% CI: 0.33, 0.86). The highest versus the lowest quartile of dietary iron increased PD risk in men (OR=1.82, 95% CI: 1.11, 2.99). When the lowest quartile of cholesterol and the highest quartile for iron were compared to the highest quartile of cholesterol and the lowest quartile of iron, no association was seen in women, but for men PD risk was increased (OR=2.70, 95% CI: 1.26, 5.76). Saturated fat intake below the median in combination with iron intake above the median also increased PD risk (OR=1.50, 95% CI: 1.07, 2.11) in both genders combined. Conclusions-A low intake of cholesterol, particularly in the presence of high iron, may be associated with an increased risk for PD.

Parkinsonism & Related Disorders, 2006

Associations of Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp... more Associations of Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (PD) with diabetes mellitus (DM) and other medical conditions were investigated in a case-control study of 352 newly diagnosed PD case and 484 control subjects. Men with DM had a significantly lower risk of PD, than men without DM (odds ratio (OR) = 0.52, 95% confidence interval (CI) = 0.28, 0.97), whereas the association in women was weaker (OR = 0.80, 95% CI = 0.35, 1.83). PD risk was reduced among male and female smokers, with and without diabetes. However, among diabetics, the PD risk was especially reduced in non-smoking men (OR = 0.09, 95% CI = 0.02, 0.44). Other medical conditions showed no strong relations with PD.

Neuroscience Letters, 2005

Reactive oxygen species derived from dopamine metabolism can induce oxidative stress and thus may... more Reactive oxygen species derived from dopamine metabolism can induce oxidative stress and thus may contribute to Parkinson's disease (PD) pathogenesis. The quinone oxidoreductases, nicotinamide adenine dinucleotide (phosphate) (NAD[P]H): quinone oxidoreductase 1 (NQO1) and dihydronicotinamide riboside (NRH): quinone oxidoreductase 2 (NQO2) detoxify quinones and quinonoid compounds. We investigated associations of genetic polymorphisms of NQO1 (C609T) and NQO2 (I/D, 29 base pairs) with PD in a population-based case-control study of 190 idiopathic PD cases and 305 unrelated controls matched on age and sex. No associations were detected for either gene variant or for any allele combinations.

Movement Disorders, 2008

Inverse associations of Parkinson's disease (PD) with cigarette smoking, coffee drinking, and non... more Inverse associations of Parkinson's disease (PD) with cigarette smoking, coffee drinking, and nonsteroidal antiinflammatory drug (NSAID) use have been reported individually, but their joint effects have not been examined. To quantify associations with PD for the individual, two-way and three-way combinations of these factors, a case-control association study with 1,186 PD patients and 928 controls was conducted. The study setting was the NeuroGenetics Research Consortium. Subjects completed a structured questionnaire regarding smoking, coffee, and NSAID consumption. Odds ratios were calculated using unconditional logistic regression. Smoking, coffee, and over the counter NSAID use as individual factors exhibited significantly reduced risks of 20% to 30%. The two-way and three-way combinations were associated with risk reduction of 37% to 49%, and 62%, respectively. Smoking and coffee exhibited significant inverse risk trends with increasing cumulative exposures, suggesting dose-response relations. With respect to the combination of all three exposures, persons who were at the highest exposure strata for smoking and coffee and used NSAIDs had an estimated 87% reduction in risk (OR ϭ 0.13, 95% CI ϭ 0.06-0.29). Whether this finding reflects true biologic protection needs to be investigated.

Journal of Neurosurgical Anesthesiology, 1997

Journal of Cardiovascular Pharmacology, 1991

Epilepsy Research, 1995

Previous experiments suggest the primary route of valproic acid (VPA) removal from the rabbit cen... more Previous experiments suggest the primary route of valproic acid (VPA) removal from the rabbit central nervous system (CNS) is by probenecid-sensitive transporters at the blood-brain barrier but not at the choroid plexus. The purpose of this study was to determine if other transport mechanisms at the choroid plexus played a significant role in the removal of VPA from the CNS. In six rabbits, silicone oil was perfused into both cerebral ventricles and out through the cistema magna to physically block exchange of VPA between cerebrospinal fluid (CSF) and blood and between brain and CSF. In six control rabbits, perfusion was performed with mock CSF. Both groups received a loading dose followed by continuous intravenous infusion of VPA for 2~L0 min. Ventriculocisternal perfusion with silicone oil had no significant effect on the steady-stale brain concentrations or brain-to-plasma concentration ratios of VPA, further confirming that efflux of VPA at the choroid plexus is negligible.

Epilepsy Research, 1996

Recently we investigated the mechanisms mediating the transport of valproic acid (VPA) between bl... more Recently we investigated the mechanisms mediating the transport of valproic acid (VPA) between blood and brain. In one study efflux of valproic acid (VPA) from rabbit brain was inhibited by probenecid. Efflux of VPA decreased when probenecid was given intravenously but not when probenecid was given by ventriculocisternal (VC) perfusion indicating that the major site of probenecid-sensitive transport was at the brain capillary endothelium and not at the choroid plexus. In another study VPA transport into rat brain was inhibited by para-aminohippurate (PAH). The purpose of the present study were to determine (a) if the efflux of VPA from rabbit brain was also inhibited by PAH, and (b) whether efflux of VPA could occur at the choroid plexus via an PAH-selective transport system. Six control rabbits received VPA by intravenous infusion and tracer concentrations of [3H]VPA and [14C]PAH by VC perfusion. Rabbits in the PAH group (n = 6) received identical treatment with VPA, tracer concentrations of [3H]VPA and [14C]PAH and, in addition, received 20 mM PAH by VC perfusion. PAH had no effect on the VC extraction ratio of [3H]VPA or the steady-state brain concentration of intravenously administered VPA. It is concluded that the efflux of VPA at the rabbit blood-brain barrier is mediated by a transporter different from the PAH-like transporter responsible for the uptake of VPA into rat brain. In addition, the finding that VC perfusion with PAH had no effect on the VC extraction of [3H]VPA provides further evidence that the choroid plexus plays a negligible role in removal of VPA from the CNS.

Brain Research, 2000

Delivery of valproic acid (VPA) to the human brain is relatively inefficient as reflected by a lo... more Delivery of valproic acid (VPA) to the human brain is relatively inefficient as reflected by a low brain-to-unbound plasma concentration ratio (#0.5) at steady state. Previous pharmacokinetic studies suggested that the unfavorable brain-to-plasma gradient is maintained by coupled efflux transport processes at both the brain parenchymal cells and blood-brain barrier (BBB); one or both of the efflux transporters are inhibitable by probenecid. The present study in rabbits utilized microdialysis to measure drug concentration in the brain extracellular fluid (ECF) of the cerebral cortex during steady-state i.v. infusion with VPA alone or with VPA plus probenecid. Probenecid co-infusion elevated VPA concentration in the brain tissue surrounding the tip of the microdialysis probe to a greater extent than in the ECF (230% versus 47%). Brain intracellular compartment (ICC) concentration was estimated. In control rabbits, the ICC concentration was 2.860.28 times higher than the ECF concentration. Probenecid co-infusion elevated the ICC-to-ECF concentration ratio to 4.260.44, which confirms the existence of an efflux transport system in brain parenchymal cells. The ECF-to-unbound plasma concentration ratio was well below unity (0.029), indicating an uphill efflux transport of VPA across the BBB. Co-infusion of probenecid did not have a significant effect on VPA efflux at the BBB as evidenced by a minimal change in the ECF-to-unbound plasma concentration ratio. This study suggests the presence of distinctly different organic anion transporters for the efflux of VPA at the parenchymal cells and capillary endothelium in the brain.

Anesthesiology, 2002

Background Consequences of volatile anesthetic degradation by carbon dioxide absorbents that cont... more Background Consequences of volatile anesthetic degradation by carbon dioxide absorbents that contain strong base include formation of compound A from sevoflurane, formation of carbon monoxide (CO) and CO toxicity from desflurane, enflurane and isoflurane, delayed inhalation induction, and increased anesthetic costs. Amsorb (Armstrong Ltd., Coleraine, Northern Ireland) is a new absorbent that does not contain strong base and does not form CO or compound A in vitro. This investigation compared Amsorb, Baralyme (Chemetron Medical Division, Allied Healthcare Products, St. Louis, MO), and sodalime effects on CO (from desflurane and isoflurane) and compound A formation, carboxyhemoglobin (COHb) concentrations, and anesthetic degradation in a clinically relevant porcine in vivo model. Methods Pigs were anesthetized with desflurane, isoflurane, or sevoflurane, using fresh or partially dehydrated Amsorb, Baralyme, and new and old formulations of sodalime. Anesthetic concentrations in the fre...

Anesthesia & Analgesia, 1998